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Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer
Jeffrey Mowat1, Rafael Carretero1,2, Gabriele Leder1
1Bayer AG, Pharmaceutical R&D, 13342 Berlin, Germany.
Abstract:
Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGFβ), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients. Here, we describe the systematic optimization of azaindole-based lead compound 1, resulting in the discovery of potent and selective MAP4K1 inhibitor 38 (BAY-405) that displays nanomolar potency in biochemical and cellular assays as well as in vivo exposure after oral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive effect of PGE2 and TGFβ. Treatment of tumor-bearing mice shows T-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction with PD-L1 blockade results in a superior antitumor impact, illustrating the complementarity of the single agent treatments.
Insights
Researchers developed BAY-405, a potent inhibitor of Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1). This drug enhances T-cell immunity against tumors and shows promise when combined with PD-L1 blockade.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a key immune checkpoint in T-cell responses.
- Tumor microenvironment factors like prostaglandin E2 (PGE2) and transforming growth factor beta (TGFβ) enhance MAP4K1 activity, suppressing anti-tumor immunity.
Purpose of the Study:
- To discover and optimize a novel pharmacological inhibitor of MAP4K1 for immuno-oncology applications.
- To evaluate the efficacy of the optimized inhibitor, BAY-405, in enhancing T-cell responses and combating cancer.
Main Methods:
- Systematic optimization of an azaindole-based lead compound to identify potent and selective MAP4K1 inhibitors.
- Biochemical, cellular, and in vivo assays to assess the potency, selectivity, and pharmacokinetic properties of BAY-405.
- Evaluation of BAY-405 efficacy in tumor-bearing mouse models, both as a single agent and in combination with PD-L1 blockade.
Main Results:
- Discovery of BAY-405, a potent and selective MAP4K1 inhibitor with nanomolar activity.
- BAY-405 demonstrated oral bioavailability and enhanced T-cell immunity, overcoming PGE2 and TGFβ-mediated suppression.
- BAY-405 treatment resulted in T-cell-dependent antitumor efficacy in mice.
- Combination therapy with BAY-405 and PD-L1 blockade yielded superior antitumor effects compared to single agents.
Conclusions:
- Pharmacological inhibition of MAP4K1 is a viable immuno-oncology strategy.
- BAY-405 is a promising clinical candidate for cancer immunotherapy.
- Combined inhibition of MAP4K1 and PD-L1 offers a synergistic approach to enhance antitumor immunity.
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